1. Field of the Invention
This invention relates generally to the field of cell-surface glycoproteins and specifically to the use of integrin B.sub.1C and cytoplasmic peptides thereof, for inhibition of cell growth.
2. Description of Related Art
Integrins are a family of cell surface glycoproteins which mediate cell-cell and cell-extracellular matrix interactions and play an important role in processes such as cell migration, tissue repair and tumor invasion (Hynes, R., Cell 48:549, 1987; Ruoslahti and Giancotti, Cancer Cells 1:119, 989). They are heterodimers composed of non-covalently linked .alpha. and .beta. subunits which associate in different combinations generating several receptor complexes with distinct binding specificities.
The .beta.1 class of integrins is found in various combinations to form integrins with different functions. For example, the .alpha.1/.beta.1 and the .alpha.2/.beta.1 are receptors for collagens; the .alpha.3/.beta.1 has broad specificity and binds to collagen, fibronectin and laminin; the .alpha.4/.beta.1 is a receptor that mediates lymphocytes-target adhesion during cytolysis as well as the interaction of lymphocytes with endothelial cells; the .alpha.5/.beta.1 and the .alpha.6/.beta.1 complexes are receptors specific for fibronectin and laminin, respectively. Both .alpha. and .beta. subunits are transmembrane proteins that provide a linkage between the extracellular matrix protein and actin, and are located in specialized areas of the plasma membrane called focal contacts (Damsky, et al., J. Cell Biol., 100:1528, 1985).
The cytoplasmic domains of the integrins play an important role in integrin functions. First, recent studies have shown that the cytoplasmic domain of the .beta.2 subunit modulates the affinity of the .alpha.L.beta.3 integrin (LFA-1) for its ligand, ICAM-1 (Hibbs, et al., Science, 251:1611, 1991). Second, tyrosine phosphorylation of the .beta.1 subunit cytoplasmic domain has been found to reduce the binding of the fibronectin receptor to fibronectin extracellularly and to talin inside the cell (Tapley, et al., Oncogene 4:325, 1989). Third, truncation of the .beta.1 subunit cytoplasmic domain can abolish the ability of the .beta.1 integrins to localize in adhesion plaques (Marcantonio, et al., Cell Reg., 1:597, 1990).
Recently, several cytoplasmic terminal variants for the human .beta.1 integrin (.beta..sub.1A) (Argraves, et al., J. Cell Biol., 105:1183, 1987) have been identified. One such variant, .beta..sub.1B described by Altruda, et al., (Gene, 95:261, 1990), is 9 amino acids shorter than the corresponding domain of .beta.1 and contains unique C-terminal sequences. A second variant, .beta..sub.1C, was identified as an alternative splice variant of .beta.1 that contains an insert of 116 nucleotides which produces a frame shift in the native .beta.1 nucleotide sequence and codes for a unique 48-amino acid C-terminus (Languino and Ruoslahti, J. Biol. Chem., 267:7116, 1992).
Although various .beta.1 integrin variants have been identified, the function for these polypeptides has been unclear. The present invention provides a biological activity for the .beta..sub.1C variant, including methods of use for the full length polypeptide as well as functional cytoplasmic fragments of the polypeptide.